Sekar Kathiresan (Verve)

Sekar Kathire­san show­cas­es his­toric mon­key da­ta in hunt for a once-and-done gene edit­ing ap­proach to pre­vent heart at­tacks

In a first for CRISPR — a field that’s seen quite a few his­toric moves in the past cou­ple of years — sci­en­tists have slashed cho­les­terol and lipid lev­els in mon­keys us­ing a tech­nique known as base edit­ing, gen­er­at­ing cru­cial proof-of-con­cept for both the biotech be­hind the ex­per­i­ment and a key part­ner.

Verve Ther­a­peu­tics de­signed two sim­i­lar ex­per­i­ments to test whether they can re­pro­duce pro­tec­tive mu­ta­tions in a pair of genes us­ing an ade­nine base ed­i­tor, which pre­cise­ly al­ters a cho­sen A to a G in the genome. CEO and co-founder Sekar Kathire­san pre­sent­ed the re­sults at a vir­tu­al keynote for the In­ter­na­tion­al So­ci­ety for Stem Cell Re­search over the week­end.

The base ed­i­tors ap­peared to have es­sen­tial­ly turned off genes, shut­ting down pro­duc­tion of cor­re­spond­ing pro­teins. That trans­lat­ed to a 60% drop in LDL with the PC­SK9 ther­a­py and a 64% plunge in triglyc­erides on the ANGPTL3 treat­ment.

When it comes to low­er­ing the col­lo­qui­al bad cho­les­terol, “60% is on par if not bet­ter than any oth­er treat­ment out there,” Kathire­san told End­points News just af­ter his pre­sen­ta­tion.

These re­sults are the cul­mi­na­tion of Kathis­er­an’s decades-long search for ge­net­ic clues for solv­ing coro­nary heart dis­ease, the lead­ing cause of death in the world. While di­rec­tor of the Cen­ter for Ge­nom­ic Med­i­cine at Mass­a­chu­setts Gen­er­al Hos­pi­tal and the Car­dio­vas­cu­lar Dis­ease Ini­tia­tive at the Broad In­sti­tute, he and col­leagues had iden­ti­fied eight genes that har­bor rare mu­ta­tions as­so­ci­at­ed with re­sis­tance to my­ocar­dial in­farc­tion. Af­ter show­ing in mice that they could ad­min­is­ter a one-time treat­ment for per­ma­nent low­er­ing of cho­les­terol, he left acad­e­mia to work on bring­ing it to hu­mans full-time.

There is, of course, still a long way to go. But Kathire­san be­lieves the new da­ta have lit up Verve’s path to the clin­ic.

They are still choos­ing be­tween the PC­SK9 and ANGPTL3 pro­grams as their lead can­di­date. Once they do — the dead­line will be the end of the year — an IND for pa­tients ge­net­i­cal­ly pre­dis­posed to high risk of heart at­tack is in sight for 2022.

Both pro­grams demon­strat­ed dra­mat­ic re­duc­tions in the tar­get pro­tein, cut­ting 89% of PC­SK9 and 95% of ANGPTL3 from the blood­stream. With the study lim­it­ed to two weeks, though, the dura­bil­i­ty ques­tions loomed large dur­ing the Q&A.

“We have en­cour­ag­ing da­ta out to sev­er­al months now,” Kathire­san said, ex­press­ing con­fi­dence that the edit­ing will be sta­ble long-term.

The rate of DNA reached 67% of the liv­er for PC­SK9 and 60% for ANGPTL3 which, Kathis­er­an point­ed out, rep­re­sents the ma­jor­i­ty of he­pa­to­cytes as around 30% of the liv­er is sup­port­ing tis­sue. Get­ting to not just ma­ture he­pa­to­cytes but al­so stem cells would be cru­cial. In pre­vi­ous re­search by oth­er groups, sci­en­tists have ob­served con­tin­ued edit­ing in mice cells even when they chop out parts of the liv­er and let it re­gen­er­ate.

Con­sid­er­ing the base ed­i­tors were de­ployed in vi­vo, safe­ty was al­so para­mount. Verve re­port­ed no off-tar­get ed­its in the 108 sites mea­sured — ow­ing, Kathire­san said, to the tech­nol­o­gy they have li­censed from Beam Ther­a­peu­tics.

Un­like the first gen­er­a­tion of CRISPR edit­ing, base edit­ing doesn’t snip at the site Cas9 brings it to; rather, through an en­zyme, it con­verts one base to an­oth­er chem­i­cal­ly.

“So it’s kind of in­ge­nious be­cause it us­es the GPS lo­cal­iza­tion fea­ture of Cas9, but it doesn’t use the dou­ble-strand break fea­ture of Cas9,” he said.

Apart from the mR­NA that forms the ed­i­tor, every Verve ther­a­py al­so con­sists of a guide RNA — picked out from hun­dreds — di­rect­ing the ma­chin­ery to the de­sired spot, all en­cap­su­lat­ed in a lipid nanopar­ti­cle en­gi­neered in col­lab­o­ra­tion with Van­cou­ver-based Acuitas.

De­liv­er­ing with lipid nanopar­ti­cles in­stead of a vi­ral vec­tor is a de­lib­er­ate choice.

“We need to get in, get the ed­i­tor and the guide RNA, get the edit­ing to hap­pen and then every­thing to go away as quick­ly as pos­si­ble,” Kathire­san said, “be­cause the longer the liv­er is ex­posed to the edit­ing ma­chin­ery, the more like­ly you are to get off-tar­get ef­fects. and lipid nanopar­ti­cles al­low de­liv­ery and then res­o­lu­tion of the process with­in a cou­ple of days.”

Al­so de­lib­er­ate is their de­ci­sion to part­ner wide­ly and as­sem­ble — not in­vent — all the tools that might aid their work. Base ed­i­tors aren’t go­ing to cov­er the full spec­trum of pos­si­ble and nec­es­sary changes as Kathire­san and his team go down their pri­or­i­tized list of eight genes. But they are tak­ing it one step at a time.

Mi­no­ryx and Sper­o­genix ink an ex­clu­sive li­cense agree­ment to de­vel­op and com­mer­cial­ize lerigli­ta­zone in Chi­na

September 23, 2020 – Hong Kong, Beijing, Shanghai (China) and Mataró, Barcelona (Spain)  

Minoryx will receive an upfront and milestone payments of up to $78 million, as well as double digit royalties on annual net sales 

Sperogenix will receive exclusive rights to develop and commercialize leriglitazone for the treatment of X-linked adrenoleukodystrophy (X-ALD), a rare life-threatening neurological condition

FDA chief Stephen Hahn on Capitol Hill earlier this week (Getty Images)

As FDA’s work­load buck­les un­der the strain, Trump again ac­cus­es the agency of a po­lit­i­cal hit job

Peter Marks appeared before a virtual SVB Leerink audience yesterday and said that his staff at FDA’s CBER is on the verge of working around the clock. Manufacturing inspections, policy work and sponsor communications have all been pushed down the to-do list so that they can be responsive to Covid-related interactions. And the agency’s objective right now? “To save as many lives as we can,” Marks said, likening the mortality on the current outbreak as equivalent to “a nuclear bomb on a small city.”

Vas Narasimhan (AP Images)

Still held down by clin­i­cal hold, No­var­tis' Zol­gens­ma falls fur­ther be­hind Bio­gen and Roche as FDA asks for a new piv­otal study

Last October, the FDA slowed down Novartis’ quest to extend its gene therapy to older spinal muscular atrophy patients by slapping a partial hold on intrathecal administration. Almost a year later, the hold is still there, and regulators are adding another hurdle required for regulatory submission: a new pivotal confirmatory study.

The new requirement — which departs significantly from Novartis’ prior expectations — will likely stretch the path to registration beyond 2021, when analysts were expecting a BLA submission. That could mean more time for Biogen to reap Spinraza revenues and Roche to ramp up sales of Evrysdi in the absence of a rival.

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Scoop: ARCH’s Bob Nelsen is back­ing an mR­NA up­start that promis­es to up­end the en­tire man­u­fac­tur­ing side of the glob­al busi­ness

For the past 2 years, serial entrepreneur Igor Khandros relied on a small network of friends and close insiders to supply the first millions he needed to fund a secretive project to master a new approach to manufacturing mRNA therapies.

Right now, he says, he has a working “GMP-in-a-box” prototype for a new company he’s building — after launching 3 public companies — which plans to spread this contained, precise manufacturing tech around the world with a set of partners. He’s raised $60 million, recruited some prominent experts. And not coincidentally, he’s going semi-public with this just as a small group of pioneers appears to be on the threshold of ushering in the world’s first mRNA vaccines to fight a worldwide pandemic.

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The win­dow is wide open as four more biotechs join the go-go IPO class of 2020

It’s another day of hauling cash in the biopharma world as four more IPOs priced Friday and a fifth filed its initial paperwork.

The biggest offering comes from PMV Pharma, an oncology biotech focusing on p53 mutations, which raised $211.8 million after pricing shares at $18 apiece. Prelude Therapeutics, developing PRMT5 inhibitors for rare cancers, was next with a $158 million raise, pricing shares at $19 each. Graybug Vision raised $90 million after pricing at $16 per share for its wet AMD candidates, and breast cancer biotech Greenwich Lifesciences brought up the rear with a small, $7 million raise after pricing shares at $5.75.

J&J of­fers PhI/IIa da­ta show­ing its sin­gle-dose vac­cine can stir up suf­fi­cient im­mune re­sponse

Days after J&J dosed the first participants of its Phase III ENSEMBLE trial, the pharma giant has detailed the early-stage data that gave them confidence in a single-dose regimen.

Testing two dose levels either as a single dose or in a two-dose schedule spaced by 56 days in, the scientists from Janssen, the J&J subsidiary developing its vaccine, reported that the low dose induced a similar immune response as the high dose. The interim Phase I/IIa results were posted in a preprint on medRxiv.

Daniel O'Day, Gilead CEO (Kevin Dietsch/UPI/Bloomberg via Getty Images)

Play-by-play of Gilead­'s $21B Im­munomedics buy­out de­tails a fren­zied push — and mints a new biotech bil­lion­aire

Immunomedics had not really been looking for a buyout when the year began. Excited by its BLA for Trodelvy, submitted to the FDA in late 2019, executive chairman Behzad Aghazadeh started off looking for potential licensing deals and zeroed in on four potential partners, including Gilead, following January’s JP Morgan Healthcare Conference in San Francisco. Such talks advanced throughout the year, with discussions advancing to the second round in mid-August.

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President Donald Trump reacts after signing an executive order following his remarks on his healthcare policies yesterday in Charlotte, North Carolina (Getty Images)

Op-ed: Will phar­ma re­al­ly pay for Trump’s lat­est law­less promise to 33 mil­lion Medicare ben­e­fi­cia­ries? Not like­ly

Sitting atop the executive branch, President Donald Trump is the ultimate authority at the FDA. He can fast track any vaccine to approval himself. If it came to that, of course.

What he can’t do is unilaterally order the legislative branch to loosen the Treasury’s coffers for $6.6 billion. Nor can he command pharmaceutical companies to pay for $200 vouchers sent to 33 million Medicare beneficiaries for prescription drugs before the election.

New York governor Andrew Cuomo (AP Images)

An­drew Cuo­mo says New York will un­der­take its own vac­cine re­view process, and wouldn’t rec­om­mend trust­ing the fed­er­al gov­ern­ment

The concerns keep mounting over President Donald Trump’s politicization of the FDA and other federal agencies guiding the development of a safe and effective vaccine. And today, the telegenic New York governor Andrew Cuomo appeared to introduce even more politics into the matter — latest in an ongoing series of incidents that have cast the proudly independent FDA in starkly political terms.

During his daily press conference Cuomo said that the state will review any coronavirus vaccines approved by the federal government, citing a lack of trust in the Trump administration. The announcement comes one day after Trump accused the FDA of making an “extremely political” move in proposing stricter vaccine guidance.